Polylactide(PLA) microspheres were prepared using the solid-in-oil(S/O) spray-drying method to achieve the sustained release of a hydrophilic drug for the treatment of tuberculosis, via intratracheal instillation. Isoniazid(IN), a low-molecular-weight hydrophilic drug, was used as a model drug. The effects of various sizes of micronized IN powder, different drug/polymer ratios, spray-drying process parameters, and drug-release characteristics were studied to optimize the manufacturing parameters. A high entrapment efficiency(87.3%) was obtained using this method; furthermore, the microspheres were spherical and smooth. They were individually and homogenously distributed, with a mean diameter of 5.6 μm; furthermore, they showed a satisfactory extended sustained-release phase. After administration of the microspheres to rats, pulmonary drug concentrations were maintained at a relatively stable level for up to 4 weeks. Polylactide (PLA) microspheres were prepared using the solid-in-oil (S / O) spray-drying method to achieve the sustained release of a hydrophilic drug for the treatment of tuberculosis, The effects of various sizes of micronized IN powder, different drug / polymer ratios, spray-drying process parameters, and drug-release characteristics were studied to optimize the manufacturing parameters. A high They were individually and homogenously distributed, with a mean diameter of 5.6 μm; furthermore, they showed a satisfactory extended sustained-release phase. After administration of the microspheres to rats, pulmonary drug concentrations were maintained at a relatively stable level for up to 4 weeks.